Role of Zn2+ Ions in Host-Virus Interactions
Maciej Lazarczyk and Michel Favre



The involvement of Zn2+ ions in the structure of ubiquitous protein zinc fingers gives this metal a particular position in the biology of the cell. Zinc has long been known as a trace element crucial for the proper folding and functioning of numerous proteins in the cell, including enzymes, signal transduction proteins, and transcription factors. However, deeper insights into the exact mechanistic role of zinc in different cellular processes, especially the physiological role of free-Zn2+ ions present in the cell, were limited, while the key elements of the cellular system regulating Zn2+ trafficking and storage remained unidentified. The discovery of the zinc binding metallothioneins (43) and the subsequent identification of the first zinc transporters in the mid-1990s (53) constituted milestones in this field, leading to a much better understanding of zinc biochemistry. Nevertheless, because of extremely low concentrations of unbound free Zn2+ in the cell, progress was long hampered by the lack of highly sensitive and specific Zn2+ indicators. Admittedly, it has been known that apart from their role in maintaining the proper zinc finger structure, free-zinc ions somehow affect a variety of signaling pathways, but only very recently has it been demonstrated that free-Zn2+ ions can serve not only as modulators of signal transduction but also as classical cellular second messengers (33, 73).
Uncovering these molecular details of zinc homeostasis in the cell has unexpectedly opened new avenues in the field of virology, shedding new light on host-virus interactions. It has long been recognized that Zn2+ is an important cofactor not only of cellular proteins but of many viral proteins as well. Recent studies demonstrated that the cellular environment itself, with its extremely small and tightly controlled pool of free zinc, may represent a limiting factor. Viruses rely on the intracellular store of zinc ions and use cellular Zn2+ for their newly synthesized proteins. Consequently, the cellular systems controlling zinc balance might constitute a natural protective barrier that limits the accessibility of zinc and thus interferes with virus replication. Indeed, disruption of this barrier, an event that naturally takes place in patients suffering from a rare genetic disease, epidermodysplasia verruciformis (EV), leads to a zinc imbalance in the cell (37) and confers an unusual sensitivity to infections by cutaneous human papillomaviruses (EV-HPVs) (51). Intriguingly, this protective barrier appears to constitute an evolutionarily conserved cellular target for viral proteins, and some viruses have developed an active mechanism that allows them to invade the cellular system managing zinc fluxes in order to maintain the desired free-zinc concentration (37, 49). These findings define a previously unknown type of host-virus interaction, further stressing the importance of cellular Zn2+ ions to the virus. However, to what extent this mechanism represents a more general phenomenon in virology remains an open question.

Here, we first present the general basis of the significance of zinc to the virus, and thereafter we discuss the molecular mechanisms of this enigmatic interplay between viruses and the cellular systems that manage Zn2+ flux, with particular emphasis on this newly discovered type of host-virus interaction.



The system that manages cellular zinc homeostasis. Cellular Zn2+ uptake is conferred by ZIP transporters (shown in green), although L-type calcium channels (LTCC) might participate in this process. An excess of unbound cytoplasmic Zn2+ is transported outside the cell by ZnT/CDF family members (shown in red), mainly ZnT-1. However, the influence of ZnT-1 on Zn2+ transport may also result from indirect suppression of Zn2+ influx through L-type calcium channels. The exact role of other ZnTs (ZnT-4 and ZnT-5) and the Na+/Zn2+ exchanger in Zn2+ efflux is not yet fully clarified and might differ, depending on cellular background. It is noteworthy that the splice variant ZnT-5b (*) constitutes the only known exception, and in contrast to other ZnT members, it might also transport Zn2+ into the cytoplasm. The cytoplasmic Zn2+ is buffered by binding to cellular proteins, metallothioneins, in particular, or is redistributed among organelles. So far, several proteins transporting Zn2+ into the Golgi apparatus have been identified (ZnT-4, ZnT-5, ZnT-6, and ZnT-7). The transfer of Zn2+ into the ER in mammalian cells is much less clarified, although the EVER/ZnT-1 complex might be involved in this process. Furthermore, a mutual exchange of Zn2+ between the ER and Golgi apparatus through antero- and retrograde vesicular transport has been postulated. Zn2+ is transported into the "vesicular compartment" by different sets of ZnT proteins, depending on the tissue context. Zn2+ possibly crosses the outer membrane of mitochondria through porin channels; subsequently, it might be bound to the metallothioneins in the intermembrane space and/or further transported to the mitochondrial matrix by not-yet-defined proteins. Zn2+ is transported in the reverse direction, from organelles to the cytosol, by ZIP family members, and ZIP1, ZIP7 (ER and Golgi apparatus), and ZIP8 (vesicles) have been implicated in this process. The arrows represent the directions of Zn2+ transport (the dashed arrows correspond to the hypothetical routes). The names of nonmammalian ER-residing transporters have been italicized. The "vesicular compartment" comprises different types of cellular vesicles (endosomes, lysosomes, synaptic vesicles, and secretory vesicles) without further distinction, depending on the tissue context.

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